{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T01:29:55Z","timestamp":1780968595181,"version":"3.54.1"},"reference-count":41,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,11]],"date-time":"2022-11-11T00:00:00Z","timestamp":1668124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003718","name":"Korea Institute of Oriental Medicine","doi-asserted-by":"publisher","award":["KSN2021330"],"award-info":[{"award-number":["KSN2021330"]}],"id":[{"id":"10.13039\/501100003718","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lophatherum gracile Bronghiart, used in traditional herbal medicine, has many biological properties including antiviral, antipyretic, antitumor, vasorelaxation, and neutrophilic inflammatory effects. However, its modulatory effects on bone metabolism have not been investigated previously. In this study, we examined the effects of a water extract of the leaves of L. gracile (WELG) on osteoclast differentiation and bone loss, and explored its underlying mechanisms. We found that WELG inhibits osteoclastogenesis by suppressing both receptor activator of nuclear factor-\u03baB ligand (RANKL)-induced early activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-\u03baB (NF-\u03baB)- and RANKL-induced modulation of the positive and negative regulators of osteoclastogenesis in osteoclast precursors. In vivo study demonstrated that WELG protects against bone loss, weight gain, and fat accumulation without affecting uterine atrophy in an ovariectomy-induced postmenopausal osteoporosis mice model. In addition, photochemical analysis of WELG identified active constituents known to have bone-protective effects. Overall, the results of this study suggest that WELG can be a potential candidate for therapy and prevention of postmenopausal osteoporosis.<\/jats:p>","DOI":"10.3390\/ijms232213942","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T02:29:32Z","timestamp":1668392972000},"page":"13942","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Lophatherum gracile Bronghiart Suppresses Receptor Activator of Nuclear Factor Kappa-B Ligand-Stimulated Osteoclastogenesis and Prevents Ovariectomy-Induced Osteoporosis"],"prefix":"10.3390","volume":"23","author":[{"given":"Sung-Ju","family":"Lee","sequence":"first","affiliation":[{"name":"KM Convergence Research Division, Korea Institute of Oriental Medicine, Yuseong-daero 1672, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seon-A","family":"Jang","sequence":"additional","affiliation":[{"name":"Future Technology Research Center, KT&G Corporation, 30, Gajeong-ro, Yuseong-gu, Daejeon 34128, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Cheol","family":"Kim","sequence":"additional","affiliation":[{"name":"KM Convergence Research Division, Korea Institute of Oriental Medicine, Yuseong-daero 1672, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Ah","family":"Ryuk","sequence":"additional","affiliation":[{"name":"KM Convergence Research Division, Korea Institute of Oriental Medicine, Yuseong-daero 1672, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunil","family":"Ha","sequence":"additional","affiliation":[{"name":"KM Convergence Research Division, Korea Institute of Oriental Medicine, Yuseong-daero 1672, Daejeon 34054, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kim, J.M., Lin, C., Stavre, Z., Greenblatt, M.B., and Shim, J.H. (2020). Osteoblast-Osteoclast Communication and Bone Homeostasis. Cells, 9.","DOI":"10.3390\/cells9092073"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.molmed.2005.11.007","article-title":"RANKL-RANK signaling in osteoclastogenesis and bone disease","volume":"12","author":"Wada","year":"2006","journal-title":"Trends Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gao, Y., Patil, S., and Jia, J. (2021). The Development of Molecular Biology of Osteoporosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158182"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1098\/rsif.2009.0282","article-title":"Perspective on post-menopausal osteoporosis: Establishing an interdisciplinary understanding of the sequence of events from the molecular level to whole bone fractures","volume":"7","author":"McNamara","year":"2010","journal-title":"J. R. Soc. Interface"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12","DOI":"10.4068\/cmj.2016.52.1.12","article-title":"Signaling Pathways in Osteoclast Differentiation","volume":"52","author":"Kim","year":"2016","journal-title":"Chonnam. Med. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"706","DOI":"10.14348\/molcells.2017.0225","article-title":"Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation","volume":"40","author":"Park","year":"2017","journal-title":"Mol. Cells"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"28355","DOI":"10.1074\/jbc.273.43.28355","article-title":"The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor","volume":"273","author":"Wong","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/sj.emboj.7600564","article-title":"RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis","volume":"24","author":"Gohda","year":"2005","journal-title":"EMBO J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.bbrc.2006.10.011","article-title":"Induction of c-Fos and NFATc1 during RANKL-stimulated osteoclast differentiation is mediated by the p38 signaling pathway","volume":"351","author":"Huang","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1172\/JCI200419657","article-title":"Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation","volume":"114","author":"Ikeda","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"18245","DOI":"10.1074\/jbc.M610701200","article-title":"NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1","volume":"282","author":"Yamashita","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/S1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1172\/JCI35711","article-title":"NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism","volume":"118","author":"Aliprantis","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/j.0105-2896.2005.00327.x","article-title":"Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system","volume":"208","author":"Tanaka","year":"2005","journal-title":"Immunol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"36277","DOI":"10.1038\/srep36277","article-title":"Ethanol extract of Lophatheri Herba exhibits anti-cancer activity in human cancer cells by suppression of metastatic and angiogenic potential","volume":"6","author":"Kim","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113224","DOI":"10.1016\/j.jep.2020.113224","article-title":"Lophatherum gracile Brongn. attenuates neutrophilic inflammation through inhibition of JNK and calcium","volume":"264","author":"Lai","year":"2021","journal-title":"J. Ethnopharm."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"983023","DOI":"10.1155\/2012\/983023","article-title":"Selected Extracts of Chinese Herbal Medicines: Their Effect on NF-\u03baB, PPAR\u03b1 and PPAR\u03b3 and the Respective Bioactive Compounds","volume":"2012","author":"Rozema","year":"2012","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1055\/s-0031-1280128","article-title":"Flavone C-glycosides from the leaves of Lophatherum gracile and their in vitro antiviral activity","volume":"78","author":"Wang","year":"2012","journal-title":"Planta Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"387","DOI":"10.3923\/ijp.2016.387.393","article-title":"Hepatoprotective Activity of Lophatherum gracile Leaves of Ethanol Extracts Against Carbon Tetrachloride-induced Liver Damage in Mice","volume":"12","author":"He","year":"2016","journal-title":"Int. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1038\/nm.2452","article-title":"Evidence for osteocyte regulation of bone homeostasis through RANKL expression","volume":"17","author":"Nakashima","year":"2011","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Xiong, J., Piemontese, M., Onal, M., Campbell, J., Goellner, J.J., Dusevich, V., Bonewald, L., Manolagas, S.C., and O\u2019Brien, C.A. (2015). Osteocytes, not Osteoblasts or Lining Cells, are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138189"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1359\/jbmr.2002.17.11.2068","article-title":"MLO-Y4 osteocyte-like cells support osteoclast formation and activation","volume":"17","author":"Zhao","year":"2002","journal-title":"J. Bone Min. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"26475","DOI":"10.1074\/jbc.M313973200","article-title":"Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos","volume":"279","author":"Matsuo","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1182\/blood-2006-09-048249","article-title":"MafB negatively regulates RANKL-mediated osteoclast differentiation","volume":"109","author":"Kim","year":"2007","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1038\/nm.2007","article-title":"Interferon regulatory factor-8 regulates bone metabolism by suppressing osteoclastogenesis","volume":"15","author":"Zhao","year":"2009","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3117","DOI":"10.1073\/pnas.0912779107","article-title":"Blimp1-mediated repression of negative regulators is required for osteoclast differentiation","volume":"107","author":"Nishikawa","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1038\/416744a","article-title":"RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta","volume":"416","author":"Takayanagi","year":"2002","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s42000-020-00216-8","article-title":"Association between HDL-C levels and menopause: A meta-analysis","volume":"20","author":"Li","year":"2021","journal-title":"Hormones"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3109\/13697137.2012.707385","article-title":"Understanding weight gain at menopause","volume":"15","author":"Davis","year":"2012","journal-title":"Climacteric"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1007\/s11914-018-0451-y","article-title":"Bone Marrow Adipose Tissue and Skeletal Health","volume":"16","author":"Muruganandan","year":"2018","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.stem.2017.02.009","article-title":"Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration","volume":"20","author":"Ambrosi","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.chroma.2013.11.015","article-title":"High-throughput and sensitive screening of compounds with deoxyribonucleic acid-binding activity by a high-performance liquid chromatography-tandem mass spectrometry-fluorescence detection technique using palmatine as a fluorescence probe","volume":"1323","author":"Fu","year":"2014","journal-title":"J. Chromatogr. A"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1592","DOI":"10.1002\/fsn3.2782","article-title":"Spectrum-effect relationship between ultra-high-performance liquid chromatography fingerprints and antioxidant activities of Lophatherum gracile Brongn","volume":"10","author":"Liu","year":"2022","journal-title":"Food Sci. Nutr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1002\/mnfr.201400592","article-title":"Rooibos flavonoids, orientin and luteolin, stimulate mineralization in human osteoblasts through the Wnt pathway","volume":"59","author":"Nash","year":"2015","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"174634","DOI":"10.1016\/j.ejphar.2021.174634","article-title":"Adiponectin receptors by increasing mitochondrial biogenesis and respiration promote osteoblast differentiation: Discovery of isovitexin as a new class of small molecule adiponectin receptor modulator with potential osteoanabolic function","volume":"913","author":"Pal","year":"2021","journal-title":"Eur. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1248\/bpb.b13-00430","article-title":"Chlorogenic acid inhibits osteoclast differentiation and bone resorption by down-regulation of receptor activator of nuclear factor kappa-B ligand-induced nuclear factor of activated T cells c1 expression","volume":"36","author":"Kwak","year":"2013","journal-title":"Biol. Pharm. Bull."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11010-007-9689-x","article-title":"Oral administration of phytocomponent p-hydroxycinnamic acid prevents bone loss in ovariectomized rats","volume":"311","author":"Yamaguchi","year":"2008","journal-title":"Mol. Cell. Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"708","DOI":"10.3892\/ijmm.2012.1043","article-title":"The bone anabolic carotenoid p-hydroxycinnamic acid promotes osteoblast mineralization and suppresses osteoclast differentiation by antagonizing NF-\u03baB activation","volume":"30","author":"Yamaguchi","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Zhou, R.P., Lin, S.J., Wan, W.B., Zuo, H.L., Yao, F.F., Ruan, H.B., Xu, J., Song, W., Zhou, Y.C., and Wen, S.Y. (2016). Chlorogenic Acid Prevents Osteoporosis by Shp2\/PI3K\/Akt Pathway in Ovariectomized Rats. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166751"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.chroma.2015.01.019","article-title":"An analysis method for simultaneous screening of deoxyribonucleic acid-binding active compounds and investigating their mechanisms by ultra-fast liquid chromatography tandem mass spectrometry coupled with fluorescence detection technology","volume":"1381","author":"Zhang","year":"2015","journal-title":"J. Chromatogr. A"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hwang, Y.H., Jang, S.A., Kim, T., and Ha, H. (2019). Forsythia suspensa Protects against Bone Loss in Ovariectomized Mice. Nutrients, 11.","DOI":"10.3390\/nu11081831"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13942\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:16:41Z","timestamp":1760145401000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/13942"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,11]]},"references-count":41,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232213942"],"URL":"https:\/\/doi.org\/10.3390\/ijms232213942","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,11]]}}}